ABCB1 基因型对新型口服抗凝药物药代动力学和临床结局的影响：系统评价和荟萃分析。
Effect of ABCB1 Genotypes on the Pharmacokinetics and Clinical Outcomes of New Oral Anticoagulants: A Systematic Review and Meta-analysis.
机构信息
Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing 100034, China.
Department of Cardiology, Peking University First Hospital, No. 8, Xi Shi Ku Street, Beijing 100034, China.
出版信息
Curr Pharm Des. 2018;24(30):3558-3565. doi: 10.2174/1381612824666181018153641.
BACKGROUND
New Oral Anticoagulants (NOACs) are effective and widely used to prevent and treat thromboembolic diseases, but the response to NOACs differs according to ABCB1 genotypes.
OBJECTIVE
We investigated the effects of ABCB1 genotypes on the pharmacokinetics and clinical outcomes of NOACs.
METHODS
We searched PubMed, Embase, and the Cochrane Library for studies on ABCB1 genotypes published from the inception of these databases until May 23, 2018. The Weighted Mean Difference (WMD) and Odds Ratio (OR) with 95% Confidence Interval (CI) were calculated for continuous and dichotomous data, respectively. Summary results were calculated using a random effects model.
RESULTS
Ten studies involving 2609 individuals were included in the systematic review, and three studies involving 535 individuals were included in the meta-analysis. Overall, four ABCB1 single-nucleotide polymorphisms were identified in the review. Carriers of the ABCB1 rs1045642 CC genotype had lower maximum plasma concentration (Cmax) than those of TT (WMD = -16.99 ng/mL; 95% CI = -33.39 to -0.59; P = 0.04), and carriers of the rs2032582 GG genotype showed lower Cmax than those of the A/T allele (WMD = -19.21 ng/mL; 95% CI = -36.62 to -1.80; P = 0.03). Carriers of the rs1045642 CC genotype showed lower area under the curve from time 0 to infinity (AUC0-∞) than those of the T allele (WMD = -78.58 ng·h/mL; 95% CI = -151.14 to -6.01; P = 0.03). ABCB1 rs4148738 genotypes did not affect the risks of ischemic stroke or systemic embolism (OR = 0.88), ischemic events (OR = 0.98), bleeding (OR = 0.94), major bleeding (OR = 1.14), or minor bleeding (OR = 0.94) in patients treated with dabigatran.
CONCLUSION
Cmax was lower in carriers of ABCB1 rs1045642 CC than in those of TT and in carriers of rs2032582 GG than in those of the A/T allele, and AUC0-∞ was lower in carriers of rs1045642 CC than in those of TT. Conversely, ABCB1 rs4148738 genotypes did not affect primary clinical endpoints in dabigatran-administered patients. Future studies should analyze the relationships of ABCB1 genotypes with the pharmacokinetics and clinical outcomes of specific NOACs.
背景
新型口服抗凝剂（NOACs）在预防和治疗血栓栓塞性疾病方面有效且应用广泛，但 ABCB1 基因型对 NOACs 的反应存在差异。
目的
我们研究了 ABCB1 基因型对 NOACs 药代动力学和临床结局的影响。
方法
我们检索了从这些数据库建立到 2018 年 5 月 23 日发表的关于 ABCB1 基因型的 PubMed、Embase 和 Cochrane 图书馆的研究。对于连续和二分类数据，分别计算加权均数差（WMD）和比值比（OR）及其 95%置信区间（CI）。使用随机效应模型计算汇总结果。
结果
系统评价纳入了 10 项涉及 2609 人的研究，荟萃分析纳入了 3 项涉及 535 人的研究。总的来说，在综述中发现了 4 个 ABCB1 单核苷酸多态性。与 TT 基因型相比，ABCB1 rs1045642 CC 基因型携带者的最大血浆浓度（Cmax）更低（WMD = -16.99 ng/mL；95%CI = -33.39 至 -0.59；P = 0.04），与 A/T 等位基因相比，rs2032582 GG 基因型携带者的 Cmax 更低（WMD = -19.21 ng/mL；95%CI = -36.62 至 -1.80；P = 0.03）。与 T 等位基因相比，ABCB1 rs1045642 CC 基因型携带者的曲线下面积从 0 到无穷大（AUC0-∞）更低（WMD = -78.58 ng·h/mL；95%CI = -151.14 至 -6.01；P = 0.03）。ABCB1 rs4148738 基因型对达比加群治疗患者的缺血性卒中和全身性栓塞（OR = 0.88）、缺血性事件（OR = 0.98）、出血（OR = 0.94）、大出血（OR = 1.14）或小出血（OR = 0.94）风险无影响。
结论
与 TT 基因型相比，ABCB1 rs1045642 CC 基因型携带者的 Cmax 更低，与 A/T 等位基因相比，rs2032582 GG 基因型携带者的 Cmax 更低，与 TT 基因型携带者相比，ABCB1 rs1045642 CC 基因型携带者的 AUC0-∞ 更低。相反，ABCB1 rs4148738 基因型对达比加群治疗患者的主要临床终点无影响。未来的研究应分析 ABCB1 基因型与特定 NOACs 药代动力学和临床结局的关系。
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